Background and Objectives
Nearly one-third of nursing home residents in the US receive antipsychotic medications, yet important questions remain concerning their safety. We sought to compare the risk of major medical events in residents newly initiated on conventional or atypical antipsychotics.
Cohort study, using linked Medicaid, Medicare, Minimum Data Set and Online Survey Certification and Reporting data. Propensity score-adjusted proportional hazards models were used to compare risks for medical events at a class and individual drug level.
Nursing homes in 45 US states.
83,959 Medicaid eligible residents ≥65 who initiated antipsychotic treatment following nursing home admission in 2001-2005.
Conventional and atypical antipsychotics.
Hospitalization for myocardial infarction, cerebrovascular events, serious bacterial infections and hip fracture within 180 days of treatment initiation.
Risks of bacterial infections (HR = 1.25, 95%CI 1.05-1.49) and possibly myocardial infarction (1.23, 95%CI 0.81-1.86) and hip fracture (1.29, 95%CI 0.95-1.76) were higher and risks of cerebrovascular events (0.82, 95%CI 0.65-1.02) were lower among patients initiating conventional compared to atypical agents. Little variation existed among individual atypical agents, except for a somewhat lower risk of cerebrovascular events with olanzapine (0.91, 95%CI 0.81-1.02) and quetiapine (0.89, 95%CI 0.79-1.02); a lower risk of bacterial infections (0.83, 95%CI 0.73-0.94) and possibly a higher risk of hip fracture (1.17, 95%CI 0.96-1.43) with quetiapine, all compared with risperidone. Dose-response relations were observed for all events (1.12, 95%CI 1.05-1.19 for high- vs low-dose for all events combined).
These associations underscore the importance of carefully selecting the specific antipsychotic agent and dose, and monitoring their safety, especially in nursing home residents who have an array of medical illnesses and receive complex medication regimens.
Antipsychotics; nursing homes; safety; dementia
A recent meta-analysis has indicated that, in patients with dementia, the use of atypical antipsychotics is associated with an excess mortality. Later observational studies have suggested that conventional antipsychotics may pose an even greater risk of death. None of these studies could evaluate the risk associated with single antipsychotics nor could they provide any conclusive evidence concerning the risk among nursing home residents. We conducted a retrospective cohort study to compare the risk of death associated with atypical and conventional antipsychotics in a large population of nursing home residents with dementia.
We identified 6,524 new users of atypical antipsychotics and 3,205 new users of conventional antipsychotics living in 1,581 Medicare- or Medicaid-certified nursing homes in 5 US states during the years 1998–2000. The outcome measure was all-cause mortality, which was determined during 6-months of follow-up.
After adjusting for potential confounders relative to users of atypicals, the rate of death was increased for users of conventional antipsychotics (hazard ratio [HR], 1.26; 95% CI, 1.13–1.42). Relative to risperidone, a higher rate of death was documented for haloperidol (HR, 1.31; 95% CI, 1.13–1.53), phenothiazines (HR, 1.17; 95% CI, 1.00–1.38) and other conventional medications (HR, 1.32; 95% CI, 0.99–1.80). No atypical antipsychotic was associated with a differential risk relative to risperidone.
Conventional antipsychotics are associated with a higher risk of all-cause mortality than atypical agents. It seems advisable that they are not used in substitution for atypical antipsychotics among nursing home residents with dementia even when short-term therapy is being prescribed.
A reporting association of risperidone with pituitary tumors has been observed. Because such tumors are highly prevalent, there may be other reasons why they were revealed in association with risperidone treatment. We assessed two potential explanations: disproportionately more prolactin assessment and head/brain imaging in risperidone-treated patients vs patients treated with other antipsychotics.
Treatment episodes with risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole, haloperidol, perphenazine and 'other typical' antipsychotics were identified in two databases (large commercial, Medicaid). Comparisons used proportional hazards regression to determine whether prolactin testing was disproportionate with risperidone, regardless of prior potentially prolactin-related adverse events (PPAEs). Logistic regression determined whether magnetic resonance imaging (MRI)/computed tomography (CT) were disproportionate in risperidone-treated patients vs other patients, regardless of hyperprolactinemia or PPAEs. In each regression, the 'other typical' antipsychotic category served as the comparator. Regression models controlled for age, gender, and other factors.
Altogether, 197,926 treatment episodes were analyzed (63,878 risperidone). Among patients with or without preceding PPAEs, risperidone treatment was associated with a significantly greater likelihood of prolactin assessment (hazard ratio (HR) 1.34, 95% confidence interval (CI) = 1.09 to 1.66, p = 0.007). Among patients with hyperprolactinemia or PPAEs, those treated with risperidone (odds ratio (OR) 1.66, 95% CI 1.23 to 2.23, p = 0.001) or ziprasidone (OR 1.66, 95% CI 1.06 to 2.62, p = 0.028) had a higher likelihood of MRI/CT.
Risperidone-treated patients are more likely to undergo prolactin assessment regardless of prior PPAEs, and more likely to undergo MRI/CT in association with hyperprolactinemia or PPAEs. Thus, a predisposition for more evaluations in risperidone-treated patients may contribute to disproportionate identification and reporting of prevalent pituitary adenoma.
This study compared 1-year risk of psychiatric hospitalization and treatment costs in commercially insured patients with bipolar disorder, treated with aripiprazole, ziprasidone, olanzapine, quetiapine or risperidone.
This was a retrospective propensity score-matched cohort study using the Ingenix Lab/Rx integrated insurance claims dataset. Patients with bipolar disorder and 180 days of pre-index enrollment without antipsychotic exposure who received atypical antipsychotic agents were followed for up to 12 months following the initial antipsychotic prescription. The primary analysis used Cox proportional hazards regression to evaluate time-dependent risk of hospitalization, adjusting for age, sex and pre-index hospitalization. Generalized gamma regression compared post-index costs between treatment groups.
Compared to aripiprazole, ziprasidone, olanzapine and quetiapine had higher risks for hospitalization (hazard ratio 1.96, 1.55 and 1.56, respectively; p < 0.05); risperidone had a numerically higher but not statistically different risk (hazard ratio 1.37; p = 0.10). Mental health treatment costs were significantly lower for aripiprazole compared with ziprasidone (p = 0.004) and quetiapine (p = 0.007), but not compared to olanzapine (p = 0.29) or risperidone (p = 0.80). Total healthcare costs were significantly lower for aripiprazole compared to quetiapine (p = 0.040) but not other comparators.
In commercially insured adults with bipolar disorder followed for 1 year after initiation of atypical antipsychotics, treatment with aripiprazole was associated with a lower risk of psychiatric hospitalization than ziprasidone, quetiapine, olanzapine and risperidone, although this did not reach significance with the latter. Aripiprazole was also associated with significantly lower total healthcare costs than quetiapine, but not the other comparators.
Sexual dysfunction is a common condition in patients taking antipsychotics, and is the most bothersome symptom and adverse drug effect, resulting in a negative effect on treatment compliance. It is known that hyperprolactinemia is a major cause of sexual dysfunction. Based on the blockade of dopamine D2 receptors, haloperidol, risperidone, and amisulpride are classed as prolactin-elevating antipsychotics, while olanzapine, clozapine, quetiapine, ziprasidone, and aripiprazole are classed as prolactin-sparing drugs. Risperidone and the other typical antipsychotics are associated with a high rate of sexual dysfunction as compared to olanzapine, clozapine, quetiapine, and aripiprazole. With regard to treatment in patients suffering from sexual dysfunction, sildenafil was associated with significantly more erections sufficient for penetration as compared to a placebo. Subsequent studies are needed in order to provide physicians with a better understanding of this problem, thereby leading toward efficacious and safe solutions.
Sexual dysfunction; Antipsychotic agents; Management
The purpose of this study was to evaluate the long-term cost-effectiveness (including hospitalizations and cardiometabolic consequences) of atypical antipsychotics among adults with schizophrenia.
A 5-year Markov cohort cost-effectiveness model, from a US payer perspective, was developed to compare lurasidone, generic risperidone, generic olanzapine, generic ziprasidone, aripiprazole, and quetiapine extended-release. Health states included in the model were patients: on an initial atypical antipsychotic; switched to a second atypical antipsychotic; and on clozapine after failing a second atypical antipsychotic. Incremental cost-effectiveness ratios (ICERs) assessed incremental cost/hospitalization avoided. Effectiveness inputs included discontinuations, hospitalizations, weight change, and cholesterol change from comparative clinical trials for lurasidone and for aripiprazole, and the Clinical Antipsychotic Trials of Intervention Effectiveness for other comparators. Atypical antipsychotic-specific relative risk of diabetes obtained from a retrospective analysis was used to predict cardiometabolic events per Framingham body mass index risk equation. Mental health costs (relapsing versus nonrelapsing patients) and medical costs associated with cardiometabolic consequences (cardiovascular events and diabetes management) were obtained from published sources. Atypical antipsychotic costs were estimated from Red Book® prices at dose(s) reported in clinical data sources used in the model (weighted average dose of lurasidone and average dose for all other comparators). Costs and outcomes were discounted at 3%, and model robustness was tested using one-way and probabilistic sensitivity analyses.
Ziprasidone, olanzapine, quetiapine extended-release, and aripiprazole were dominated by other comparators and removed from the comparative analysis. ICER for lurasidone versus risperidone was $25,884/relapse-related hospitalization avoided. At a $50,000 willingness-to-pay threshold, lurasidone has an 86.5% probability of being cost-effective, followed by a 7.2% probability for olanzapine, and 6.3% for risperidone. One-way sensitivity analysis showed the model is sensitive to lurasidone and generic risperidone hospitalization rates.
Generic risperidone is the least costly atypical antipsychotic. Lurasidone is more costly and more effective than risperidone and is cost-effective at willingness-to-pay thresholds of greater than $25,844 per hospitalization avoided. The favorable cost-effectiveness of lurasidone is driven by its clinical benefits (eg, efficacy in preventing hospitalizations in patients with schizophrenia) and its minimal cardiometabolic adverse effect profile.
cost-effectiveness; economic; model; schizophrenia; atypical antipsychotic
Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment.
We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic.
Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test.
Mean QTc intervals significantly increased in Group 2 (24 ± 21 ms) however this was not the case in Group 1 (-1 ± 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05).
No significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.
antipsychotic; antidepressant; proarrhythmia; QTc interval
CONVENTIONAL ANTIPSYCHOTIC DRUGS, used for a half century to treat a range of major psychiatric disorders, are being replaced in clinical practice by modern “atypical” antipsychotics, including aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone among others. As a class, the newer drugs have been promoted as being broadly clinically superior, but the evidence for this is problematic. In this brief critical overview, we consider the pharmacology, therapeutic effectiveness, tolerability, adverse effects and costs of individual modern agents versus older antipsychotic drugs. Because of typically minor differences between agents in clinical effectiveness and tolerability, and because of growing concerns about potential adverse long-term health consequences of some modern agents, it is reasonable to consider both older and newer drugs for clinical use, and it is important to inform patients of relative benefits, risks and costs of specific choices.
This study examined a cohort of Medicaid patients with new prescriptions for atypical antipsychotic medication to determine the prevalence of sub-therapeutic atypical antipsychotic medication use and to identify patient and prescribing provider characteristics associated with its occurrence.
This observational cohort study examined Medicaid administrative claims data for patients age 20–64 with a new prescription for an atypical antipsychotic medication (clozapine, olanzapine, quetiapine, risperidone, ziprasidone) between 1/2004 and 12/2004. Patient characteristics, prescribing provider characteristics, length of therapy, and dosing were examined. A logistic regression assessed the probability of sub-therapeutic dosing.
Among 830 individuals starting an atypical antipsychotic, only 15% had a documented diagnosis of schizophrenia, sub-therapeutic dosing was common (up to 86% of patients taking quetiapine), and 40% of the sample continued less than 30 days with the indexed prescription. A logistic model indicated that a general practitioner as prescribing provider, length of therapy less than 30 days, and prescription of quetiapine were significantly associated with a sub-therapeutic dose.
These results suggest there is extensive use of expensive atypical anti-psychotic medications for off-label purposes such as sedation or for other practice patterns that should be explored further. Approaches that minimize off-label atypical antipsychotic use could be of considerable value to Medicaid programs. In addition, theses findings support the need for the introduction or increased use of utilization monitoring, and the implementation of medication practice guidelines as appropriate decision support for prescribing providers.
antipsychotic medication; prescribing practices; practice parameters
The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na+, Ca2+ and K+ channels often leading to life-threatening arrhythmia.
To overcome the toxicity of old generation of antidepressants and antipsychotics, selective serotonin reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) were introduced during the past decade. Although these new compounds are not more effective in treating psychiatric disorders than older medications, they gained incredible popularity since they have been reported to have fewer and more benign side effect profile (including cardiovascular) than predecessors.
Surprisingly, an increasing number of case reports have demonstrated that the use of SSRIs and new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram (ECG) and orthostatic hypotension in patients lacking cardiovascular disorders, raising new concerns about the putative cardiovascular safety of these compounds. In agreement with these clinical reports these new compounds indeed show marked cardiovascular depressant effects in different mammalian and human cardiovascular preparations by inhibiting cardiac and vascular Na+, Ca2+ and K+ channels. Taken together, these results suggest that the new generation of antidepressants and antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with cardiovascular disorders.
The primary goal of this review is to shed light on the recently observed clinically important cardiovascular effects of new antidepressants and antipsychotics and discuss the mechanism beyond this phenomenon.
antidepressants; neuroleptics; antipsychotics; QT prolongation; arrhythmia; cardiac ion channels; repolarization
Coronary artery disease (CAD) is highly prevalent in nursing home residents and is associated with a substantial clinical and economic burden. Statins reduce mortality and hospitalization rates in older patients with CAD.
To assess rates and predictors of statin use among high-risk patients with symptomatic coronary artery disease (CAD) admitted to nursing homes after acute cardiac hospitalization.
Medicare beneficiaries enrolled in either a state-run drug assistance program or Medicaid in nursing homes in New Jersey from 1994 through 2005.
Statin utilization within 60 days of nursing home admission was determined for patients recently hospitalized with symptomatic CAD in whom statins are indicated consisting of those with: acute coronary syndrome (ACS) without revascularization, ACS with revascularization and congestive heart failure (CHF) with revascularization. Predictors of statin use were evaluated with multivariate logistic regression models.
While statin use over the 11-year period increased from 1.2% to 31.8%, overall utilization was very low. Predictors of greater statin use included prior cardiac hospitalization [odds ratio (OR) 1.32, 95% confidence interval (95% CI) 1.13 to 1.57], prior statin use (OR 6.92, 95% CI 5.86 to 8.82) and receipt of a concurrent cardiac medication (range of odds ratios, 2.36–3.40). Older patients admitted for ACS with or without revascularization were less likely to receive a statin. Patients who had received anti-platelets or angiotensin-modifying agents prior to their hospitalization were less likely to receive statins after discharge. Renal disease, prior stroke, diabetes, hypertension and hyperlipidemia did not influence statin utilization. Predictors of treatment did not change when the cohort was dichotomized according to length of stay.
Patients are infrequently treated with statins when discharged to nursing homes following hospitalization for a symptomatic cardiovascular event. Barriers to statin treatment in this setting require closer examination.
geriatrics; drugs; pharmacoepidemiology; prevention
Effectiveness of a drug is a key concept dependent on efficacy, safety, and tolerability. Time to discontinuation of treatment is also representative of effectiveness. We investigated differences in treatment discontinuation among newly started second-generation antipsychotics in the clinical setting.
Using a retrospective cohort study design, we screened all outpatients (n = 7936) who visited the Shioiri Mental Clinic between July 1, 2008 and June 30, 2010. We identified a cohort of patients (n = 703) diagnosed with schizophrenia or schizoaffective disorder and calculated the time to discontinuation of each second-generation antipsychotic.
Of the 703 patients, 149 were newly treated with aripiprazole, 67 with blonanserin, 95 with olanzapine, 36 with quetiapine, 74 with perospirone, and 120 with risperidone. The time to discontinuation for all causes was significantly longer for aripiprazole than for blonanserin, olanzapine, and risperidone. In addition, aripiprazole tended to be continued for longer than quetiapine and perospirone, but these differences were not significant.
Aripiprazole may be considered the best available option for long-term treatment of patients with schizophrenia or schizoaffective disorder.
retrospective study; second-generation antipsychotics; effectiveness; treatment continuation; schizophrenia; aripiprazole
Tardive dyskinesia (TD) rates with second-generation antipsychotics (SGAs) are considered to be low relative to first-generation antipsychotics (FGAs), even in the particularly vulnerable elderly population. However, risk estimates are unavailable for patients naïve to FGAs. Therefore, we aimed to determine the TD incidence in particularly vulnerable, antipsychotic-naïve elderly patients treated with the SGA risperidone or olanzapine. The present work describes a prospective inception cohort study of antipsychotic-naïve elderly patients aged ⩾55 years identified at New York Metropolitan area in-patient and out-patient geriatric psychiatry facilities and nursing homes at the time of risperidone or olanzapine initiation. At baseline, 4 weeks, and at quarterly periods, patients underwent assessments of medical and medication history, abnormal involuntary movements, and extra-pyramidal signs. TD was classified using Schooler–Kane criteria. Included in the analyses were 207 subjects (age: 79.8 years, 70.0% female, 86.5% White), predominantly diagnosed with dementia (58.9%) or a major mood disorder (30.9%), although the principal treatment target was psychosis (78.7%), with (59.4%) or without (19.3%) agitation. With risperidone (n=159) the cumulative TD rate was 5.3% (95% confidence interval (CI): 0.7, 9.9%) after 1 year (mean dose: 1.0±0.76 mg/day) and 7.2% (CI: 1.4, 12.9%) after 2 years. With olanzapine (n=48) the cumulative TD rate was 6.7% (CI: 0, 15.6%) after 1 year (mean dose: 4.3±1.9 mg/day) and 11.1% (CI: 0, 23.1%) after 2 years. TD risk was higher in females, African Americans, and patients without past antidepressant treatment or with FGA co-treatment. The TD rates for geriatric patients treated with risperidone and olanzapine were comparable and substantially lower than previously reported for similar patients in direct observation studies using FGAs. This information is relevant for all patients receiving antipsychotics, not just the especially sensitive elderly.
tardive dyskinesia; antipsychotics; olanzapine; risperidone; elderly; cohort study; movement disorders; aging/geriatrics; schizophrenia/antipsychotics; tardive dyskinesia; olanzapine; risperidone; cohort study
Use of atypical antipsychotics (AA) in combination with an antidepressant is recommended as an augmentation strategy for patients with depression. However, there is a paucity of data comparing aripiprazole and other AAs in terms of patient reported outcomes. Therefore, the objective of this study was to examine the levels of HRQoL and health utility scores in patients with depression using aripiprazole compared with patients using olanzapine, quetiapine, risperidone and ziprasidone.
Data were obtained from the 2009, 2010, and 2011 National Health and Wellness Survey (NHWS), a cross-sectional, internet-based survey that is representative of the adult US population. Only those patients who reported being diagnosed with depression and taking an antidepressant and an atypical antipsychotic for depression were included. Patients taking an atypical antipsychotic for less than 2 months or who reported being diagnosed with bipolar disorder or schizophrenia were excluded. Patients taking aripiprazole were compared with patients taking other atypical antipsychotics. Health-related quality of life (HRQoL) and health utilities were assessed using the Short Form 12-item (SF-12) health survey. Differences between groups were analyzed using General Linear Models (GLM) controlling for demographic and health characteristics.
Overall sample size was 426 with 59.9% taking aripiprazole (n = 255) and 40.1% (n = 171) taking another atypical antipsychotic (olanzapine (n = 19), quetiapine (n = 127), risperidone (n = 14) or ziprasidone (n = 11)). Of the SF-12 domains, mean mental component summary (MCS) score (p = .018), bodily pain (p = .047), general health (p = .009) and emotional role limitations (p = .009) were found to be significantly higher in aripiprazole users indicating better HRQoL compared to other atypical antipsychotics. After controlling for demographic and health characteristics, patients taking aripiprazole reported significantly higher mean mental SF-12 component summary (34.10 vs. 31.43, p = .018), bodily pain (55.19 vs. 49.05, p = .047), general health (50.05 vs. 43.07, p = .009), emotional role limitations (49.44 vs. 41.83, p = .009), and SF-6D utility scores (0.59 vs. 0.56, p = .042).
Comparison of patients taking aripiprazole with a cohort of patients using another AA for depression demonstrated that aripiprazole was independently associated with better (both statistically and clinically) HRQoL and health utilities.
The treatment of mania starts with a correct diagnosis and elementary measures to prevent risks for the patient, relatives, and others. Sometimes, compulsory admission and treatment may be required for a few days. Patients with psychotic or mixed mania may be more difficult to treat. At the present time, there is solid evidence supporting the use of lithium, the anticonvulsants valproate and carbamazepine, and the antipsychotics chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and asenapine in acute mania, and some evidence supporting the use of clozapine or electroconvulsive therapy in treatment-refractory cases. However, in clinical practice, combination therapy is the rule rather than the exception. The treatment of acute mania deserves a long-term view, and the evidence base for some treatments may be stronger than for others. When taking decisions about treatment, tolerabiliiy should also be a major concern, as differences in safety and tolerability may exceed differences in efficacy for most compounds, Psychoeducation of patients and caregivers is a povi/erful tool that should be used in combination with medication for optimal long-term outcome. Functional recovery should be the ultimate goal.
mania; lithium; anticonvulsants; antipsychotics; clinical trials; bipolar disorder
We have carried out a bibliometric study on the scientific publications in relation to atypical or second-generation antipsychotic drugs (SGAs) in South Korea.
With the EMBASE and MEDLINE databases, we selected those publications made in South Korea whose title included the descriptors atypic* (atypical*) antipsychotic*, second-generation antipsychotic*, clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied some bibliometric indicators of paper production and dispersion with Price's law and Bradford's law, respectively. We also calculated the participation index (PI) of the different countries, and correlated the bibliometric data with some social and health data from Korea (such as total per capita expenditure on health and gross domestic expenditure on research and development).
We collected 326 original papers published between 1993 and 2011. Our results state fulfilment of fulfilled Price's law, with scientific production on SGAs showing exponential growth (correlation coefficient r=0.8978, as against an r=0.8149 after linear adjustment). The most widely studied drugs were risperidone (91 papers), aripiprazole (77), olanzapine (53), and clozapine (43). Division into Bradford zones yielded a nucleus occupied by the Progress in Neuro-Psychopharmacology and Biological Psychiatry (36 articles). A total of 86 different journals were published, with 4 of the first 10 used journals having an impact factor being greater than 4.
The publications on SGAs in South Korea have undergone exponential growth over the studied period, without evidence of reaching a saturation point.
Second-generation antipsychotics; Atypical antipsychotics; Bibliometry; Schizophrenia; Bipolar disorder; South Korea
Scant information exists to guide pharmacological treatment of early-onset schizophrenia. We examine variation across commonly prescribed second-generation antipsychotic medications in medication discontinuation and psychiatric hospital admission among children and adolescents clinically diagnosed with schizophrenia. A 45-state Medicaid claims file (2001–2005) was analyzed focusing on outpatients, aged 6–17 years, diagnosed with schizophrenia or a related disorder prior to starting a new episode of antipsychotic monotherapy with risperidone (n = 805), olanzapine (n = 382), quetiapine (n = 260), aripiprazole (n = 173), or ziprasidone (n = 125). Cox proportional hazard regressions estimated adjusted hazard ratios of 180-day antipsychotic medication discontinuation and 180-day psychiatric hospitalization for patients treated with each medication. During the first 180 days following antipsychotic initiation, most youth treated with quetiapine (70.7%), ziprasidone (73.3%), olanzapine (73.7%), risperidone (74.7%), and aripirazole (76.5%) discontinued their medication (χ2 = 1.69, df = 4, P = .79). Compared with risperidone, the adjusted hazards of antipsychotic discontinuation did not significantly differ for any of the 4-comparator medications. The percentages of youth receiving inpatient psychiatric treatment while receiving their initial antipsychotic medication ranged from 7.19% (aripiprazole) to 9.89% (quetiapine) (χ2 = 0.79, df = 4, P = .94). As compared with risperidone, the adjusted hazard ratio of psychiatric hospital admission was 0.96 (95% CI: 0.57–1.61) for olanzapine, 1.03 (95% CI: 0.59–1.81) for quetiapine, 0.85 (95% CI: 0.43–1.70) for aripiprazole, and 1.22 (95% CI: 0.60–2.51) for ziprasidone. The results suggest that rapid antipsychotic medication discontinuation and psychiatric hospital admission are common in the community treatment of early-onset schizophrenia. No significant differences were detected in risk of either adverse outcome across 5 commonly prescribed second-generation antipsychotic medications.
schizophrenia; child psychiatry; antipsychotics; comparative effectiveness
Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac risk, and torsade de pointes.
To examine the associations between antipsychotics and 1) outpatient-originated sudden cardiac death and ventricular arrhythmia (SD/VA) and 2) all-cause death.
Two retrospective cohort studies
Medicaid programs of California, Florida, New York, Ohio and Pennsylvania.
Incident antipsychotic users aged 30–75 years.
Main Outcome Measures
1) Incident, first-listed emergency department or principal inpatient SD/VA diagnoses; and 2) death reported in the Social Security Administration Death Master File.
Among 459,614 incident antipsychotic users, the incidences of SD/VA and death were 3.4 and 35.1 per 1,000 person-years, respectively. Compared to olanzapine as the referent, adjusted hazard ratios (HRs) for SD/VA were 2.06 (95% CI, 1.20–3.53) for chlorpromazine, 1.72 (1.28–2.31) for haloperidol, and 0.73 (0.57–0.93) for quetiapine. Adjusted HRs for perphenazine and risperidone were consistent with unity. In a subanalysis limited to first prescription exposures, HRs for chlorpromazine and haloperidol were further elevated (2.54 [1.07–5.99] and 2.68 [1.59–4.53], respectively), with the latter exhibiting a dose-response relationship. Results for death were similar.
Haloperidol and chlorpromazine had less favorable cardiac safety profiles than olanzapine. Among atypical agents, risperidone had a similar cardiac safety profile to olanzapine, whereas quetiapine was associated with 30% and 20% lower risks of SD/VA and death, respectively, compared to olanzapine. These measured risks do not correlate well with average QT prolongation, further supporting the notion that average QT prolongation may be a poor surrogate of antipsychotic arrhythmogenicity.
Antipsychotic agents; Cardiac arrhythmias; Cohort studies; Death; International classification of diseases; Medicaid; Pharmacoepidemiology; Proportional hazards models; Sudden death; Torsades de pointes
Selective prescribing of conventional antipsychotic medication (APM) to frailer patients is thought to have led to overestimation of the association with mortality in pharmacoepidemiologic studies relying on claims data. The authors assessed the validity of different analytic techniques to address such confounding. The cohort included 82,012 persons initiating APM use after admission to a nursing home in 45 states with 2001–2005 Medicaid/Medicare data, linked to clinical data (Minimum Data Set) and institutional characteristics. The authors compared the association between APM class and 180-day mortality with multivariate outcome modeling, propensity score (PS) adjustment, and instrumental variables. The unadjusted risk difference (per 100 patients) of 10.6 (95% confidence interval (CI): 9.4, 11.7) comparing use of conventional medication with atypical APM was reduced to 7.8 (95% CI: 6.6, 9.0) and 7.0 (95% CI: 5.8, 8.2) after PS adjustment and high-dimensional PS (hdPS) adjustment, respectively. Results were similar in analyses limited to claims-based Medicaid /Medicare variables (risk difference = 8.2 for PS, 7.1 for hdPS). Instrumental-variable estimates were imprecise (risk difference = 8.8, 95% CI: −1.3, 19.0) because of the weak instrument. These results suggest that residual confounding has a relatively small impact on the effect estimate and that hdPS methods based on claims alone provide estimates at least as good as those from conventional analyses using claims enriched with clinical information.
antipsychotic agents; confounding factors (epidemiology); dementia; mortality; nursing homes; pharmacoepidemiology
To examine the hospitalization rate and mortality associated with forced mass transfer of nursing home residents with the highest levels of functional impairment.
Retrospective cohort study.
119 Texas and Louisiana nursing homes that were identified as being “at-risk” for evacuation for Hurricane Gustav.
6,464 long-stay residents residing in “at-risk” nursing homes for at least three consecutive months prior to landfall of Hurricane Gustav.
Using Medicare claims and instrumental variable analysis, we compared the differential mortality (death at 30 and 90 days) and hospitalization rates (at 30 and 90 days) of the most functionally-impaired long-stay residents who evacuated for Hurricane Gustav relative to the most functionally impaired residents who did not evacuate.
Results suggest that the effect of evacuation was associated with an 8% increase in hospitalizations by 30 and 90 days for the most functionally impaired residents. Evacuation was not significantly related to mortality for the most functionally impaired residents.
Our results suggest that the most functionally impaired nursing home residents experience an increase in hospitalizations but not mortality as a consequence of forced mass transfer. With the inevitability of nursing home evacuations for many different reasons, harm mitigation strategies focused on the most impaired residents are needed.
Nursing Home; Transitions; Hurricane
We conducted meta-analyses of findings from randomized, placebo-controlled, short-term trials for acute mania in manic or mixed states of DSM (III–IV) bipolar I disorder in 56 drug–placebo comparisons of 17 agents from 38 studies involving 10 800 patients. Of drugs tested, 13 (76%) were more effective than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperdone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone. Their pooled effect size for mania improvement (Hedges' g in 48 trials) was 0.42 (confidence interval (CI): 0.36–0.48); pooled responder risk ratio (46 trials) was 1.52 (CI: 1.42–1.62); responder rate difference (RD) was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat of 6 (all p<0.0001). In several direct comparisons, responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate, or carbamazepine; lithium did not differ from valproate, nor did second generation antipsychotics differ from haloperidol. Meta-regression associated higher study site counts, as well as subject number with greater placebo (not drug) response; and higher baseline mania score with greater drug (not placebo) response. Most effective agents had moderate effect-sizes (Hedges' g=0.26–0.46); limited data indicated large effect sizes (Hedges' g=0.51–2.32) for: carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen. The findings support the efficacy of most clinically used antimanic treatments, but encourage more head-to-head studies and development of agents with even greater efficacy.
antimanic; antipsychotic; mania; mood stabilizer; placebo; mood; anxiety; stress disorders; clinical pharmacology; clinical trials; psychopharmacology; drug discovery; development; mania; antimanic; mood stabilizer; antipsychotic; placebo
The Centers for Medicare and Medicaid Services (CMS) publishes a web-based quality report card for nursing homes. The quality measures (QMs) do not assess quality of end-of-life (EOL) care, which affects a large proportion of residents. This study developed prototype EOL QMs that can be calculated from data sources available for all nursing homes nationally.
The study included approximately 1.5 million decedents residing in 16,000 nursing homes during 2003–2007, nationally. Minimum Data Set (MDS) data were linked to Medicare enrollment files, hospital claims, and hospice claims. Random effect logistic models were estimated to develop risk-adjustment models predicting two outcome measures (place of death [POD] and hospice enrollment), which were then used to construct two EOL QMs. The distributional properties of the QMs were investigated.
The QMs exhibited moderate stability over time. They were more stable in identifying quality outliers among the larger nursing homes and in identifying poor-quality outliers than high-quality outliers.
This study offers two QMs specialized to EOL care in nursing homes that can be calculated from data that are readily available and could be incorporated in the Nursing Home Compare (NHC) report card. Further work to validate the QMs is required.
Despite concerns over the potential for severe adverse events, antipsychotic medications remain the mainstay of treatment of behaviour disorders and psychosis in elderly patients. Second-generation antipsychotic agents (SGAs; e.g., risperidone, olanzapine, quetiapine) have generally shown a better safety profile compared to the first-generation agents (FGAs; e.g., haloperidol and phenothiazines), particularly in terms of a lower potential for involuntary movement disorders. Risperidone, the only SGA with an official indication for the management of inappropriate behaviour in dementia, has emerged as the antipsychotic most commonly prescribed to older patients. Most clinical trials evaluating the risk of movement disorders in elderly patients receiving antipsychotic therapy have been of limited sample size and/or of relatively short duration. A few observational studies have produced inconsistent results.
A population-based retrospective cohort study of all residents of the Canadian province of Manitoba aged 65 and over, who were dispensed antipsychotic medications for the first time during the time period from April 1, 2000 to March 31, 2007, was conducted using Manitoba's Department of Health's administrative databases. Cox proportional hazards models were used to determine the risk of extrapyramidal symptoms (EPS) in new users of risperidone compared to new users of FGAs.
After controlling for potential confounders (demographics, comorbidity and medication use), risperidone use was associated with a lower risk of EPS compared to FGAs at 30, 60, 90 and 180 days (adjusted hazard ratios [HR] 0.38, 95% CI: 0.22–0.67; 0.45, 95% CI: 0.28–0.73; 0.50, 95% CI: 0.33–0.77; 0.65, 95% CI: 0.45–0.94, respectively). At 360 days, the strength of the association weakened with an adjusted HR of 0.75, 95% CI: 0.54–1.05.
In a large population of elderly patients the use of risperidone was associated with a lower risk of EPS compared to FGAs.
To compare Medicare payments of nursing home residents triaged to nursing home with those of nursing home residents triaged to the hospital for acute infection care.
Observational study with propensity score matching.
Fifty-nine nursing homes in Maryland.
Two thousand two hundred eighty-five individuals admitted to the 59 nursing homes and followed between 1992 and 1997.
Demographic and clinical data were obtained from interviews and medical record review and linked to Medicare payment records. Incident infection was ascertained according to medical record review for new infectious diagnoses or prescription of antibiotics. Hospital triage was defined as hospital transfer within 3 days of infection onset. Hospital triage patients were paired with similar nursing home triage patients using propensity score matching. Medicare expenditures for triage groups were compared in 1997 dollars.
Of 3,618 infection cases, 28% were genitouri-nary infections, 20% skin, 14% upper respiratory, 12% lower respiratory, 4% gastrointestinal, and 2% bloodstream. Two hundred fifty-six pairs of hospital and nursing home triage cases fulfilled matching criteria. Mean Medicare payments ± standard deviation were $5,202 ± 7,310 and $996 ± 2,475 per case in the hospital and nursing home triage groups, respectively, for a mean difference of $4,206 (95% confidence interval = $3,260–5,151). Mean payments per case in the hospital triage group were $3,628 higher in inpatient expenditures, $482 higher in physician visit expenditures, $161 higher in emergency department expenditures, and $147 higher in skilled nursing day expenditures.
Per-case Medicare expenditures are higher with hospital triage than for nursing home triage for nursing home residents with acute infection. This result may be used to estimate cost savings to Medicare of interventions designed to reduce hospital use by nursing home residents.
infection; nursing homes; health expenditures; Medicare
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes.
Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments.
Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33–41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall).
Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study.
Schizophrenia; clinical trial; antipsychotic; effectiveness